AIM: To study the effects of presenilin-1 (PS-1), presenilin-2 (PS-2), and amyloid beta-protein precursor (APP695)on delayed rectifier potassium channels (IK) in the cultured rat hippocampal neurons. METHODS: PS-1, PS-2, and APP695 were transfected into the cultured rat hippocampal neurons by transient transfection techniques. The IK current was observed by the whole cell patch-clamp techniques. RESULTS: IK was increased in cultured rat hippocampal neurons, after transient transfection of PS-l, PS-2, and APP695. IK amplitudes and densities were significantly increased from (1689±412) pA, (48± 18) pA/pF (mock cells, GFP alone, n= 17) to (5565± 1403) pA,(252± 107) pA/pF (PS- 1/GFP, n=22, P＜0.01), (3804± 1651 ) pA, ( 120±58) pA/pF( PS-2/GFP, n= 16, P＜0.01 ), and (4978±904) pA, (218±70) pA/pF (APP695, n=22, P＜0.01). But PS-1, PS-2, and APP695 did not alter the activation curve of IK (P＞0.05). CONCLUSION: Overexpression of PS-1, PS-2, and APP695 increased IK in the cultured rat hippocampal neurons. The upregulation of IK may be related to neuronal apoptosis after PS- 1, PS-2,and APP695 were transfected.